tbuckley/cabot-search huggingface dataset:
Evidence that direct inhibition of transcription factor binding is the prevailing mode of gene and repeat repression by DNA methylation
Authors: Sebastian Kaluscha, Silvia Domcke, Christiane Wirbelauer, Michael B. Stadler, Sevi Durdu, Lukas Burger, Dirk Schübeler
Journal: Nature Genetics (2022)

Cytosine methylation efficiently silences CpG-rich regulatory regions of genes and repeats in mammalian genomes. To what extent this entails direct inhibition of transcription factor (TF) binding versus indirect inhibition via recruitment of methyl-CpG-binding domain (MBD) proteins is unclear. Here we show that combinatorial genetic deletions of all four proteins with functional MBDs in mouse embryonic stem cells, derived neurons or a human cell line do not reactivate genes or repeats with methylated promoters. These do, however, become activated by methylation-restricted TFs if DNA methylation is removed. We identify several causal TFs in neurons, including ONECUT1, which is methylation sensitive only at a motif variant. Rampantly upregulated retrotransposons in methylation-free neurons feature a CRE motif, which activates them in the absence of DNA methylation via methylation-sensitive binding of CREB1. Our study reveals methylation-sensitive TFs in vivo and argues that direct inhibition, rather than indirect repression by the tested MBD proteins, is the prevailing mechanism of methylation-mediated repression at regulatory regions and repeats.
Reply to Mandal <i>et al.</i>
Authors: Salvatore Maurizio Maggiore, Domenico Luca Grieco, Samir Jaber, Massimo Antonelli
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

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Error in Author Affiliation
Authors: Fabio Conforti'
Journal: JAMA Network Open (2022)

Laura Pala, MD; Isabella Sala, MSc; Chiara Oriecuia, MSc; Tommaso De Pas, MD; Paola Queirolo, MD; Claudia Specchia, PhD; Emilia Cocorocchio, MD; Pierfrancesco Ferrucci, MD; Damiano Patanè, MD; Maristella Saponara, MD; Elisabetta Pennacchioli, MD; Sara Coppola, MD; Giuseppe Viale, MD; Giuseppe Giaccone, PhD, MD; Richard D. Gelber, PhD; Vincenzo Bagnardi, PhD; Fabio Conforti, MD
MYC Overexpression Drives Immune Evasion in Hepatocellular Carcinoma That Is Reversible through Restoration of Proinflammatory Macrophages
Authors: Renumathy Dhanasekaran, Aida S. Hansen, Jangho Park, Lea Lemaitre, Ian Lai, Nia Adeniji, Sibu Kuruvilla, Akanksha Suresh, Josephine Zhang, Varsha Swamy, Dean W. Felsher
Journal: Cancer Research (2022)

Abstract Cancers evade immune surveillance, which can be reversed through immune-checkpoint therapy in a small subset of cases. Here, we report that the MYC oncogene suppresses innate immune surveillance and drives resistance to immunotherapy. In 33 different human cancers, MYC genomic amplification and overexpression increased immune-checkpoint expression, predicted nonresponsiveness to immune-checkpoint blockade, and was associated with both Th2-like immune profile and reduced CD8 T-cell infiltration. MYC transcriptionally suppressed innate immunity and MHCI-mediated antigen presentation, which in turn impeded T-cell response. Combined, but not individual, blockade of PDL1 and CTLA4 could reverse MYC-driven immune suppression by leading to the recruitment of proinflammatory antigen-presenting macrophages with increased CD40 and MHCII expression. Depletion of macrophages abrogated the antineoplastic effects of PDL1 and CTLA4 blockade in MYC-driven hepatocellular carcinoma (HCC). Hence, MYC is a predictor of immune-checkpoint responsiveness and a key driver of immune evasion through the suppression of proinflammatory macrophages. The immune evasion induced by MYC in HCC can be overcome by combined PDL1 and CTLA4 blockade. Significance: Macrophage-mediated immune evasion is a therapeutic vulnerability of MYC-driven cancers, which has implications for prioritizing MYC-driven hepatocellular carcinoma for combination immunotherapy.
Confronting the consequences of racism, xenophobia, and discrimination on health and health-care systems
Authors: Ibrahim Abubakar, Lu Gram, Sarah Lasoye, E Tendayi Achiume, Laia Becares, Gurpreet Kaur Bola, Rageshri Dhairyawan, Gideon Lasco, Martin McKee, Yin Paradies, Nidhi S Sabharwal, Sujitha Selvarajah, Geordan Shannon, Delan Devakumar
Journal: The Lancet (2022)
Gut microbiota promotes stem cell differentiation through macrophage and mesenchymal niches in early postnatal development
Authors: Ji-Eun Kim, Bo Li, Lijiang Fei, Rachael Horne, Dorothy Lee, Adrian Kwan Ho Loe, Hiromu Miyake, Eda Ayar, Maria Gurma, Dae-Kyum Kim, Michael G. Surette, Dana J. Philpott, Philip Sherman, Guoji Guo, Agostino Pierro, Tae-Hee Kim
Journal: Immunity (2022)
Dapagliflozin in heart failure with improved ejection fraction: a prespecified analysis of the DELIVER trial
Authors: Orly Vardeny, James C. Fang, Akshay S. Desai, Pardeep S. Jhund, Brian Claggett, Muthiah Vaduganathan, Rudolf A. de Boer, Adrian F. Hernandez, Carolyn S. P. Lam, Silvio E. Inzucchi, Felipe A. Martinez, Mikhail N. Kosiborod, David DeMets, Eileen O’Meara, Shelley Zieroth, Josep Comin-Colet, Jaroslaw Drozdz, Chern-En Chiang, Masafumi Kitakaze, Magnus Petersson, Daniel Lindholm, Anna Maria Langkilde, John J. V. McMurray, Scott D. Solomon
Journal: Nature Medicine (2022)

Abstract With modern treatments for heart failure with reduced ejection fraction (EF), indicative of impaired cardiac systolic function, patients may exhibit an increase in EF. Limited data are available regarding the clinical management of this growing population, categorized as heart failure with improved EF (HFimpEF), which has a high event rate and has been excluded from virtually all prior heart failure outcomes trials. In a prespecified analysis of the DELIVER trial ( NCT03619213 ), of a total of 6,263 participants with symptomatic heart failure and a left ventricular EF &gt;40%, 1,151 (18%) had HFimpEF, defined as patients whose EF improved from ≤40% to &gt;40%. Participants were randomized to 10 mg dapagliflozin or placebo daily and the primary outcome of the trial was a composite of cardiovascular death or worsening heart failure (heart failure hospitalization or an urgent heart failure visit). Participants with HFimpEF had similar event rates to those with an EF consistently &gt;40%. In participants with HFimpEF, dapagliflozin reduced the primary composite outcome (hazard ratio (HR) = 0.74, 95% confidence interval (CI) = 0.56–0.97), first worsening heart failure events (HR = 0.84, 95% CI = 0.61–1.14), cardiovascular death (HR = 0.62, 95% CI = 0.41–0.96) and total worsening heart failure events (rate ratio = 0.68, 95% CI = 0.50–0.94) to a similar extent as for individuals with an EF consistently &gt;40%. These data suggest that patients with HFimpEF who are symptomatic may benefit from the addition of a sodium/glucose cotransporter 2 inhibitor to previously instituted guideline-directed medical therapy to further reduce morbidity and mortality.
Tet2- and Tet3-Mediated Cytosine Hydroxymethylation in Six2 Progenitor Cells in Mice Is Critical for Nephron Progenitor Differentiation and Nephron Endowment
Authors: Xiujie Liang, Tamas Aranyi, Jianfu Zhou, Yuting Guan, Hailong Hu, Hongbo Liu, Katalin Susztak
Journal: Journal of the American Society of Nephrology (2022)

Significance Statement Epigenetic changes have been proposed to mediate nephron endowment during development, a critical determinant of future renal disease development. Hydroxymethyl cytosine, an epigenetic modification important for gene regulation, is abundant in the human kidney, but its physiologic role and the role of DNA demethylase enzymes encoded by the Tet1 , Tet2 , or Tet3 , which mediate cytosine hydroxymethylation, are unclear. By genetically deleting Tet1 , Tet2 , or Tet3 in nephron progenitors in mice, the authors showed that combined Tet2 and Tet3 loss in nephron progenitors cause defective kidney development, leading to kidney failure and perinatal death. Tet2 and Tet3 deletion also caused an alteration in demethylation and expression of genes critical for nephron formation. These findings establish that Tet2- and Tet3 -mediated cytosine hydroxymethylation in nephron progenitors plays a critical role in nephron endowment. Background Nephron endowment is a key determinant of hypertension and renal disease in later life. Epigenetic changes have been proposed to mediate fetal programming and nephron number. DNA cytosine methylation, which plays a critical role in gene regulation, is affected by proteins encoded by the ten-eleven translocation (TET) DNA demethylase gene family ( Tet1 , Tet2 , and Tet3 ), but the roles of TET proteins in kidney development and nephron endowment have not been characterized . Methods To study whether epigenetic changes—specifically, active DNA hydroxymethylation mediated by Tet1 , Tet2 , and Tet3— are necessary for nephron progenitor differentiation and nephron endowment, we generated mice with deletion of Tet1 , Tet2 , or Tet3 in Six2-positive nephron progenitors cells (NPCs). We then performed unbiased omics profiling, including whole-genome bisulfite sequencing on isolated Six2-positive NPCs and single-cell RNA sequencing on kidneys from newborn mice. Results We did not observe changes in kidney development or function in mice with NPC-specific deletion of Tet1 , Tet2 , Tet3 or Tet1 / Tet2 , or Tet1 / Tet3 . On the other hand, mice with combined Tet2 and Tet3 loss in Six2-positive NPCs failed to form nephrons, leading to kidney failure and perinatal death. Tet2 and Tet3 loss in Six2 -positive NPCs resulted in defective mesenchymal to epithelial transition and renal vesicle differentiation. Whole-genome bisulfite sequencing, single-cell RNA sequencing, and gene and protein expression analysis identified a defect in expression in multiple genes, including the WNT- β -catenin signaling pathway, due to a failure in demethylation of these loci in the absence of Tet2 and Tet3 . Conclusions These findings suggest that Tet2- and Tet3 -mediated active cytosine hydroxymethylation in NPCs play a key role in kidney development and nephron endowment.
Carbon dots nanophotosensitizers with tunable reactive oxygen species generation for mitochondrion-targeted type I/II photodynamic therapy
Authors: Yunxiu Zhang, Qingyan Jia, Fuchun Nan, Jian Wang, Ke Liang, Jian Li, Xiaokuang Xue, Haohui Ren, Weimin Liu, Jiechao Ge, Pengfei Wang
Journal: Biomaterials (2022)
A Novel Computational Biomechanics Framework to Model Vascular Mechanopropagation in Deep Bone Marrow
Authors: Yunduo Charles Zhao, Yingqi Zhang, Fengtao Jiang, Chi Wu, Boyang Wan, Ruhma Syeda, Qing Li, Bo Shen, Lining Arnold Ju
Journal: Advanced Healthcare Materials (2022)

The mechanical stimuli generated by body exercise can be transmitted from cortical bone into the deep bone marrow (mechanopropagation). Excitingly, a mechanosensitive perivascular stem cell niche is recently identified within the bone marrow for osteogenesis and lymphopoiesis. Although it is long known that they are maintained by exercise-induced mechanical stimulation, the mechanopropagation from compact bone to deep bone marrow vasculature remains elusive of this fundamental mechanobiology field. No experimental system is available yet to directly understand such exercise-induced mechanopropagation at the bone-vessel interface. To this end, taking advantage of the revolutionary in vivo 3D deep bone imaging, an integrated computational biomechanics framework to quantitatively evaluate the mechanopropagation capabilities for bone marrow arterioles, arteries, and sinusoids is devised. As a highlight, the 3D geometries of blood vessels are smoothly reconstructed in the presence of vessel wall thickness and intravascular pulse pressure. By implementing the 5-parameter Mooney-Rivlin model that simulates the hyperelastic vessel properties, finite element analysis to thoroughly investigate the mechanical effects of exercise-induced intravascular vibratory stretching on bone marrow vasculature is performed. In addition, the blood pressure and cortical bone bending effects on vascular mechanoproperties are examined. For the first time, movement-induced mechanopropagation from the hard cortical bone to the soft vasculature in the bone marrow is numerically simulated. It is concluded that arterioles and arteries are much more efficient in propagating mechanical force than sinusoids due to their stiffness. In the future, this in-silico approach can be combined with other clinical imaging modalities for subject/patient-specific vascular reconstruction and biomechanical analysis, providing large-scale phenotypic data for personalized mechanobiology discovery.
Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline
Authors: Emrullah Yilmaz, Nofisat Ismaila, Julie E. Bauman, Raetasha Dabney, Gregory Gan, Richard Jordan, Marnie Kaufman, Kedar Kirtane, Sean Matthew McBride, Matthew O. Old, Lisa Rooper, Nabil F. Saba, Siddharth Sheth, Rathan M. Subramaniam, Trisha Michel Wise-Draper, Deborah Wong, Loren K. Mell
Journal: Journal of Clinical Oncology (2022)

To provide evidence-based recommendations for practicing physicians and other health care providers on immunotherapy and biomarker testing for head and neck cancers.ASCO convened an Expert Panel of medical oncology, surgical oncology, radiation oncology, radiology, pathology, and patient advocacy experts to conduct a literature search, including systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 2000 through 2022. Outcomes of interest included survival, overall response, and locoregional control. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations.The literature search identified 28 relevant studies to inform the evidence base for this guideline.When possible, evidence-based recommendations were developed to address biomarker testing, first-line treatment regimens based on programmed death ligand-1 scores, immunotherapy in platinum-refractory recurrent or metastatic head and neck squamous cell carcinoma, immunotherapy in nasopharyngeal carcinoma, and radiation therapy in combination with immunotherapy for treatment of local recurrence.Additional information is available at www.asco.org/head-neck-cancer-guidelines.
Antagonistic control of seed dormancy in rice by two bHLH transcription factors
Authors: Fan Xu, Jiuyou Tang, Shengxing Wang, Xi Cheng, Hongru Wang, Shujun Ou, Shaopei Gao, Boshu Li, Yangwen Qian, Caixia Gao, Chengcai Chu
Journal: Nature Genetics (2022)
Correction: YY1 Complex Promotes Quaking Expression via Super-Enhancer Binding during EMT of Hepatocellular Carcinoma
Authors: Jingxia Han, Jing Meng, Shuang Chen, Xiaorui Wang, Shan Yin, Qiang Zhang, Huijuan Liu, Rong Qin, Zhongwei Li, Weilong Zhong, Chao Zhang, Heng Zhang, Yuanhao Tang, Wanfeng Gao, Xiaoyun Zhang, Lan Yang, Yanrong Liu, Hong-gang Zhou, Tao Sun, Cheng Yang
Journal: Cancer Research (2022)

In the original version of this article (1), there were errors in Fig. 3E and the Materials and Methods section. Specifically, in Fig. 3E, the incorrect images were used to show invasion of Control, p65-transfected, YY1-transfected, and p65+YY1-transfected Hep3B cells. In the “Experimental metastasis assay” section of the Materials and Methods, the word “intratumor” was mistakenly used and the statement should read, “The YY1+p65+siQKI group was treated every 3 days with the intravenous injection of shQKI viral suspension (50 μL) and continuously injected thrice.” The correct images have been provided, and the errors have been corrected in the latest online HTML and PDF versions of the article. The authors regret these errors.
How do we collect good-quality data on race and ethnicity and address the trust gap?
Authors: Rohini Mathur, Christopher T Rentsch, Kavita Venkataraman, Segun Fatumo, Modou Jobe, Chaisiri Angkurawaranon, Suan Ee Ong, Angel Y S Wong, Moneeza K Siddiqui
Journal: The Lancet (2022)
Intersectional insights into racism and health: not just a question of identity
Authors: Geordan Shannon, Rosemary Morgan, Zahra Zeinali, Leanne Brady, Marcia Thereza Couto, Delan Devakumar, Ben Eder, Ozge Karadag, Mala Mukherjee, Maria Fernanda Tourinho Peres, Marcelo Ryngelblum, Nidhi Sabharwal, Amos Schonfield, Pamela Silwane, David Singh, Manya Van Ryneveld, Siyasanga Vilakati, Chelsea Watego, Eleanor Whyle, Kui Muraya
Journal: The Lancet (2022)
New roles for AP-1/JUNB in cell cycle control and tumorigenic cell invasion via regulation of cyclin E1 and TGF-β2
Authors: Beatriz Pérez-Benavente, Alihamze Fathinajafabadi, Lorena de la Fuente, Carolina Gandía, Arantxa Martínez-Férriz, José Miguel Pardo-Sánchez, Lara Milián, Ana Conesa, Octavio A Romero, Julián Carretero, Rune Matthiesen, Isabelle Jariel-Encontre, Marc Piechaczyk, Rosa Farràs
Journal: Genome biology (2022)

JUNB transcription factor contributes to the formation of the ubiquitous transcriptional complex AP-1 involved in the control of many physiological and disease-associated functions. The roles of JUNB in the control of cell division and tumorigenic processes are acknowledged but still unclear.
Phase IIa Study of SurVaxM Plus Adjuvant Temozolomide for Newly Diagnosed Glioblastoma
Authors: Manmeet S. Ahluwalia, David A. Reardon, Ajay P. Abad, William T. Curry, Eric T. Wong, Sheila A. Figel, Laszlo L. Mechtler, David M. Peereboom, Alan D. Hutson, Henry G. Withers, Song Liu, Ahmed N. Belal, Jingxin Qiu, Kathleen M. Mogensen, Sanam S. Dharma, Andrew Dhawan, Meaghan T. Birkemeier, Danielle M. Casucci, Michael J. Ciesielski, Robert A. Fenstermaker
Journal: Journal of Clinical Oncology (2022)

PURPOSE Despite intensive treatment with surgery, radiation therapy, temozolomide (TMZ) chemotherapy, and tumor-treating fields, mortality of newly diagnosed glioblastoma (nGBM) remains very high. SurVaxM is a peptide vaccine conjugate that has been shown to activate the immune system against its target molecule survivin, which is highly expressed by glioblastoma cells. We conducted a phase IIa, open-label, multicenter trial evaluating the safety, immunologic effects, and survival of patients with nGBM receiving SurVaxM plus adjuvant TMZ following surgery and chemoradiation (ClinicalTrials.gov identifier: NCT02455557 ). METHODS Sixty-four patients with resected nGBM were enrolled including 38 men and 26 women, in the age range of 20-82 years. Following craniotomy and fractionated radiation therapy with concurrent TMZ, patients received four doses of SurVaxM (500 μg once every 2 weeks) in Montanide ISA-51 plus sargramostim (granulocyte macrophage colony-stimulating factor) subcutaneously. Patients subsequently received adjuvant TMZ and maintenance SurVaxM concurrently until progression. Progression-free survival (PFS) and overall survival (OS) were reported. Immunologic responses to SurVaxM were assessed. RESULTS SurVaxM plus TMZ was well tolerated with no serious adverse events attributable to SurVaxM. Of the 63 patients who were evaluable for outcome, 60 (95.2%) remained progression-free 6 months after diagnosis (prespecified primary end point). Median PFS was 11.4 months and median OS was 25.9 months measured from first dose of SurVaxM. SurVaxM produced survivin-specific CD8+ T cells and antibody/immunoglobulin G titers. Apparent clinical benefit of SurVaxM was observed in both methylated and unmethylated patients. CONCLUSION SurVaxM appeared to be safe and well tolerated. The combination represents a promising therapy for nGBM. For patients with nGBM treated in this manner, PFS may be an acceptable surrogate for OS. A large randomized clinical trial of SurVaxM for nGBM is in progress.
Usp22 is an intracellular regulator of systemic emergency hematopoiesis
Authors: Nikolaus Dietlein, Xi Wang, Jonas Metz, Olivier Disson, Fuwei Shang, Celine Beyersdörffer, Esther Rodríguez Correa, Daniel B. Lipka, Yvonne Begus-Nahrmann, Robyn Laura Kosinsky, Steven A. Johnsen, Marc Lecuit, Thomas Höfer, Hans-Reimer Rodewald
Journal: Science Immunology (2022)

Emergency hematopoiesis is a concerted response aimed toward enhanced protection from infection, involving multiple cell types and developmental stages across the immune system. Despite its importance, the underlying molecular regulation remains poorly understood. The deubiquitinase USP22 regulates the levels of monoubiquitinated histone H2B (H2Bub1), which is associated with activation of interferon responses upon viral infection. Here, we show that in the absence of infection or inflammation, mice lacking Usp22 in all hematopoietic cells display profound systemic emergency hematopoiesis, evident by increased hematopoietic stem cell proliferation, myeloid bias, and extramedullary hematopoiesis. Functionally, loss of Usp22 results in elevated phagocytosis by neutrophilic granulocytes and enhanced innate protection against Listeria monocytogenes infection. At the molecular level, we found this state of emergency hematopoiesis associated with transcriptional signatures of myeloid priming, enhanced mitochondrial respiration, and innate and adaptive immunity and inflammation. Augmented expression of many inflammatory genes was linked to elevated locus-specific H2Bub1 levels. Collectively, these results demonstrate the existence of a tunable epigenetic state that promotes systemic emergency hematopoiesis in a cell-autonomous manner to enhance innate protection, identifying potential paths toward immune enhancement.
Population-level contribution of interpersonal discrimination to psychological distress among Australian Aboriginal and Torres Strait Islander adults, and to Indigenous–non-Indigenous inequities: cross-sectional analysis of a community-controlled First Nations cohort study
Authors: Katherine A Thurber, Makayla-May Brinckley, Roxanne Jones, Olivia Evans, Kirsty Nichols, Naomi Priest, Shuaijun Guo, David R Williams, Gilbert C Gee, Grace Joshy, Emily Banks, Joanne Thandrayen, Bernard Baffour, Janine Mohamed, Tom Calma, Raymond Lovett
Journal: The Lancet (2022)
Self-intensified synergy of a versatile biomimetic nanozyme and doxorubicin on electrospun fibers to inhibit postsurgical tumor recurrence and metastasis
Authors: Yongwei Hu, Yanteng Xu, Rachel L Mintz, Xing Luo, Youqiang Fang, Yeh-Hsing Lao, Hon Fai Chan, Kai Li, Shixian Lv, Guojun Chen, Yu Tao, Yun Luo, Mingqiang Li
Journal: Biomaterials (2022)